title: Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions.
abstract: BACKGROUND
  Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and despite state-of-the-art treatment, survival remains poor and novel therapeutics are sorely needed. The aim of the present study was to identify new synergistic drug pairs for GBM. In addition, we aimed to explore differences in drug-drug interactions across multiple GBM-derived cell cultures and predict such differences by use of transcriptional biomarkers.
  
  
  METHODS
  We performed a screen in which we quantified drug-drug interactions for 465 drug pairs in each of the 5 GBM cell lines U87MG, U343MG, U373MG, A172, and T98G. Selected interactions were further tested using isobole-based analysis and validated in 5 glioma-initiating cell cultures. Furthermore, drug interactions were predicted using microarray-based transcriptional profiling in combination with statistical modeling.
  
  
  RESULTS
  Of the 5 × 465 drug pairs, we could define a subset of drug pairs with strong interaction in both standard cell lines and glioma-initiating cell cultures. In particular, a subset of pairs involving the pharmaceutical compounds rimcazole, sertraline, pterostilbene, and gefitinib showed a strong interaction in a majority of the cell cultures tested. Statistical modeling of microarray and interaction data using sparse canonical correlation analysis revealed several predictive biomarkers, which we propose could be of importance in regulating drug pair responses.
  
  
  CONCLUSIONS
  We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases.
authors.affiliation: Corresponding Author: Sven Nelander, PhD, Immunology, Genetics and Pathology (IGP), Uppsala University; and Science for Life Laboratory, SE-751 85 Uppsala, Sweden.. sven.nelander@igp.uu.se.
authors.forename: Linnéa
authors.initials: L
authors.lastname: Schmidt
authors.forename: Teresia
authors.initials: T
authors.lastname: Kling
authors.forename: Naser
authors.initials: N
authors.lastname: Monsefi
authors.forename: Maja
authors.initials: M
authors.lastname: Olsson
authors.forename: Caroline
authors.initials: C
authors.lastname: Hansson
authors.forename: Sathishkumar
authors.initials: S
authors.lastname: Baskaran
authors.forename: Bo
authors.initials: B
authors.lastname: Lundgren
authors.forename: Ulf
authors.initials: U
authors.lastname: Martens
authors.forename: Maria
authors.initials: M
authors.lastname: Häggblad
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg Nilsson
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
authors.forename: Linda
authors.initials: L
authors.lastname: Karlsson-Lindahl
authors.forename: Philip
authors.initials: P
authors.lastname: Gerlee
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004347:Drug Interactions; D000077156:Gefitinib; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D011799:Quinazolines / Q000627:therapeutic use; D020280:Sertraline / Q000627:therapeutic use; D013267:Stilbenes / Q000627:therapeutic use
chemical_list: D002227:Carbazoles; D011799:Quinazolines; D013267:Stilbenes; C107773:pterostilbene; C034931:rimcazole; D020280:Sertraline; D000077156:Gefitinib
keywords: drug combination responses; glioblastoma stem cell cultures; glioblastoma therapy; predictive medicine